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1090 Vol 14 November 2014 Articles Ribavirin and interferon alfa 2a for severe Middle East respiratory syndrome coronavirus infection a retrospective cohort study Ali S Omrani Mustafa M Saad Kamran Baig Abdelkarim Bahloul Mohammed Abdul Matin Amal Y Alaidaroos Ghaleb A Almakhlafi Mohammed M Albarrak Ziad A Memish Ali M Albarrak Summary Background Middle East respiratory syndrome coronavirus MERS CoV infection is associated with high mortality and has no approved antiviral therapy We aimed to compare ribavirin and interferon alfa 2a treatment for patients with severe MERS CoV infection with a supportive therapy only Methods In this retrospective cohort study we included adults aged 16 years with laboratory confi rmed MERS CoV infection and pneumonia needing ventilation support diagnosed between Oct 23 2012 and May 1 2014 at the Prince Sultan Military Medical City Riyadh Saudi Arabia All patients received appropriate supportive care and regular clinical and laboratory monitoring but patients diagnosed after Sept 16 2013 were also given oral ribavirin dose based on calculated creatinine clearance for 8 10 days and subcutaneous pegylated interferon alfa 2a 180 g per week for 2 weeks The primary endpoint was 14 day and 28 day survival from the date of MERS CoV infection diagnosis We used and Fischer s exact test to analyse categorical variables and the t test to analyse continuous variables Findings We analysed 20 patients who received ribavirin and interferon treatment group initiated a median of 3 days range 0 8 after diagnosis and 24 who did not comparator group Baseline clinical and laboratory characteristics were similar between groups apart from baseline absolute neutrophil count which was signifi cantly lower in the comparator group 5 88 10 L SD 3 95 vs 9 88 10 L 6 63 p 0 023 14 70 of 20 patients in the treatment group had survived after 14 days compared with seven 29 of 24 in the comparator group p 0 004 After 28 days six 30 of 20 and four 17 of 24 respectively had survived p 0 54 Adverse e ects were similar between groups apart from reduction in haemoglobin which was signifi cantly greater in the treatment group than in the comparator group 4 32 g L SD 2 47 vs 2 14 g L 1 90 p 0 002 Interpretation In patients with severe MERS CoV infection ribavirin and interferon alfa 2a therapy is associated with signifi cantly improved survival at 14 days but not at 28 days Further assessment in appropriately designed randomised trials is recommended Funding None Introduction Since it was fi rst described in September 2012 855 cases of Middle East respiratory syndrome coronavirus MERS CoV infection have been confi rmed 333 of which were fatal 1 2 Cases occur sporadically as community clusters or as hospital outbreaks and range in severity from asymptomatic or mild illness to rapidly progressive and fatal disease 2 6 The management of patients with MERS CoV infection consists of a combination of supportive measures antimicrobial therapy for any associated bacterial or viral infections and strict implementation of appropriate infection control precautions 7 So far no antiviral therapy has been approved for the treatment of patients with MERS CoV infection 8 Several therapeutic interventions for coronavirus were investigated during the large multinational outbreak of severe acute respiratory syndrome SARS in 2003 9 10 Reviews of the available scientifi c literature suggest that a combination of ribavirin and interferon might be of benefi t in patients with severe MERS CoV infection 8 11 12 Further more this combination was shown to inhibit MERS CoV in cell culture and seemed to improve outcomes in an animal study 13 14 Both agents are associated with substantial potential adverse e ects and hence their clinical use should be carefully balanced against any potential harm 8 We aimed to assess outcomes of a treatment pro gramme for patients with severe MERS CoV infection that consisted of oral ribavirin and subcutaneous pegylated interferon alfa 2a We report the results and outcomes in patients given treatment in accordance with this protocol by comparison with a historical group who received supportive therapy only Methods Study design and participants This single centre retrospective cohort study included individuals who were diagnosed with laboratory confi rmed MERS CoV infection between Oct 23 2012 Lancet Infect Dis 2014 14 1090 95 Published Online September 30 2014 http dx doi org 10 1016 S1473 3099 14 70920 X See Comment page 1030 Division of Infectious Diseases A S Omrani FRCP M M Saad MD A Bahloul MD A Y Alaidaroos MD A M Albarrak FRCPC Department of Infection Prevention and Control K Baig MPH A Y Alaidaroos MD Department of Medicine M Abdul Matin FRCP and Department of Critical Care G A Almakhlafi MD M M Albarrak FRCPC Prince Sultan Military Medical City Riyadh Saudi Arabia and Al Faisal University and Ministry of Health Riyadh Saudi Arabia Prof Z A Memish FRCPC Correspondence to Dr Ziad Memish Al Faisal University PO Box 54146 Riyadh 11514 Saudi Arabia zmemish Articles Vol 14 November 2014 1091 and May 1 2014 at the Prince Sultan Military Medical City Riyadh Saudi Arabia Eligible patients were those aged 16 years or older with severe pneumonia needing invasive or non invasive ventilation No exclusion criteria were applied at this stage MERS CoV infection was diagnosed by RT PCR testing of respiratory tract samples for MERS CoV upE ORF 1b and N genes 15 All RT PCR tests for MERS CoV were done at the Saudi Ministry of Health Regional Laboratory in Jeddah and Riyadh Saudi Arabia Pneumonia was defi ned as new otherwise unexplained lower respiratory tract symptoms such as cough or shortness of breath with at least one systemic feature such as fever or chills and new focal chest signs on examination in addition to new or progressive pulmonary infi ltrates on chest radiograph 16 From Sept 16 2013 all eligible patients were o ered treatment with oral ribavirin and subcutaneous pegylated interferon alfa 2a after informed written consent had been obtained from the patients themselves or their next of kin The treatment protocol was approved by Pharmacy and Therapeutics Committee The study was approved by the Research Ethics Committee at the Prince Sultan Military Medical City to allow retrospective access to patients records and fi les Procedures Pegylated interferon alfa 2a Pegasys Roche Pharma ceuticals Basel Switzerland was given by subcutaneous injection at a dose of 180 g per week for 2 weeks The dose of oral ribavirin Copegus Roche Pharmaceuticals was adjusted according to calculated creatinine clearance and continued for 8 10 days 12 Patients with a creatinine clearance of greater than 0 833 mL sec m 2 received a 2000 mg loading dose followed by 1200 mg every 8 h for 4 days then 600 mg every 8 h for 4 6 days those with a creatinine clearance of 0 333 0 833 mL sec m received a 2000 mg loading dose followed by 600 mg every 8 h for 4 days then 200 mg every 6 h for 4 6 days and those with a creatinine clearance of 0 333 mL sec m or on dialysis received a 2000 mg loading dose followed by 200 mg every 6 h for 4 days then 200 mg every 12 h for 4 6 days Patients did not receive ribavirin and interferon alfa 2a therapy if they were diagnosed before Sept 16 2013 or if they declined consent All patients received appropriate supportive care such as supplementary oxygen vaso pressor therapy and renal replacement as needed Hydrocortisone 200 mg daily was given to patients with refractory septic shock and continued until vasopressor therapy was no longer needed 17 In addition to regular clinical monitoring renal function liver enzymes and blood count were assessed at baseline and daily throughout the treatment course Conscious patients were monitored for any clinical signs of depression or acute confusion Patients who received ribavirin and interferon alfa 2a therapy were classifi ed as being in the treatment group and those who did not made up the comparator group Two investigators ASO and KB both of whom were masked to group allocation and the patients clinical outcomes compared baseline characteristics of the two groups Treatment group n 20 Comparator group n 24 p value Men 16 75 16 67 0 323 Age years 67 4 18 5 64 0 18 1 0 54 Critical care support 20 100 24 100 Congestive heart failure 5 26 7 29 0 84 Dementia 1 5 1 4 1 00 Chronic obstructive pulmonary disease 2 10 4 17 0 67 Asthma 1 5 0 0 45 Rheumatological disease 1 5 1 4 1 00 Chronic liver disease 0 3 13 0 24 Diabetes mellitus 14 70 16 67 0 81 Hemiplegia 5 26 6 25 1 00 Chronic kidney disease 4 21 7 29 0 73 Malignant disorder 1 5 1 4 1 00 HIV infection 0 0 Obesity 1 8 4 21 0 63 Number of comorbidities 2 50 1 4 2 92 1 7 0 4 Immunosuppressive therapy 1 5 4 18 0 66 Haemoglobin g L 11 46 2 80 10 28 2 20 0 124 Peripheral white cell count 10 L 7 86 4 50 10 96 6 83 0 090 Absolute neutrophil count 10 L 5 88 3 95 9 88 6 63 0 023 Lymphocyte count 10 L 1 53 2 88 1 00 0 59 0 380 Platelet count 10 L 190 85 90 55 207 17 142 03 0 660 Alanine transaminase IU L 35 75 28 50 35 63 40 52 0 991 Aspartate transaminase IU L 689 63 2707 43 63 91 53 52 0 273 Serum bilirubin mol L 18 45 25 17 38 20 80 97 0 301 Alkaline phosphatase IU L 115 10 106 13 183 13 159 34 0 111 Serum creatinine mol L 133 75 81 72 142 38 73 18 0 714 Serum albumin g L 26 95 4 72 26 39 5 02 0 710 APACHE II score 25 31 11 40 27 94 9 20 0 479 SOFA score 10 38 4 15 12 38 4 38 0 195 Data are number or mean SD APACHE II Acute Physiology and Chronic Health Evaluation II SOFA Sequential Organ Failure Assessment Only 19 patients were assessed Only 13 patients were assessed Only 22 patients were assessed Table 1 Baseline characteristics on day of diagnosis of Middle East respiratory syndrome coronavirus infection by patient group 70 had laboratory confirmed MERS CoV infections 22 received ribavirin and interferon alfa 2a 2 did not need ventilation support 1 was aged 16 years 20 did not need ventilation support 3 had baseline renal failure 48 did not receive ribavirin and interferon alfa 2a 20 in treatment group 24 in comparator group Figure 1 Study profi le Articles 1092 Vol 14 November 2014 Outcomes The primary endpoints for the study were 14 day and 28 day survival from the date of MERS CoV infection was diagnosis Statistical analysis We used and Fischer s exact tests for categorical variables whereas we used the student s t test for continuous variables to assess the di erences in means of the two groups The log rank test was used for assess ing survival di erences between the two groups Our cuto for statistical signifi cance was 0 05 The graphical and statistical tests suggested that the pro portional hazard assumption was not violated We did statistical analyses using Microsoft Excel 2011 and Stata Statistical Software Release 12 Role of funding source No external funding was received for this study ZM had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication Results 70 individuals were diagnosed with MERS CoV infection between Oct 23 2012 and May 1 2014 Baseline characteristics were generally similar between patients who received ribavirin and interferon alfa 2a therapy and those who did not table 1 with the exception that end stage renal failure was present in three patients who did not receive study treatment and in none who did After excluding ineligible patients 44 patients were included in the study 20 in the treatment group and 24 in the comparator group fi gure 1 The mean age of all 44 patients was 65 5 years SD 18 2 and 32 73 were men table 1 The median number of comorbidities was three range 0 6 Mean Acute Physiology and Chronic Health Evaluation II APACHE II score was 27 SD 10 28 and mean Sequential Organ Failure Assessment SOFA score was 11 4 32 Mean blood indices on the day of MERS CoV diagnosis include haemoglobin 10 81 g dL SD 2 53 g dL peripheral white cell count 9 55 10 L 6 03 10 L absolute neutrophil count 8 06 10 L 5 87 10 L lymphocyte count 1 24 10 L 1 98 10 L platelets 199 75 10 L 120 33 10 L alanine transaminase 35 68 IU L 35 17 IU L aspartate transaminase 346 98 IU L 1821 82 IU L alkaline phosphatase 152 2 IU L 140 46 IU L bilirubin 29 22 mol L 62 34 mol L serum creatinine 138 45 mol L 76 38 mol L and serum albumin 26 65 g L 4 83 g L Overall 41 93 of 44 patients needed invasive ventilation whereas three patients 7 needed bilevel positive airway pressure 22 50 of all patients needed renal replacement therapy All patients received broad spectrum antibacterial therapy and 33 75 also received oseltamivir In the treatment group ribavirin and pegylated interferon alfa 2a were started within a median of 3 days range 0 8 from diagnosis of MERS CoV infection Mean absolute neutrophil count was signifi cantly lower in the treatment group than in the comparator group table 1 however no other statistically signifi cant dif ferences in baseline characteristics or support measures were noted between the two groups tables 1 2 Of all 44 patients 21 48 were still alive 14 days after diagnosis of MERS CoV infection whereas at 28 days only ten 23 had survived 14 70 of 20 patients in the treatment group were alive 14 days after diagnosis compared with seven 29 of 24 in the comparator group p 0 004 However six 30 of 20 patients in the treatment group survived up to 28 days from diagnosis of MERS CoV infection whereas four 17 of 24 did in the comparator group p 0 54 fi gure 2 Ribavirin and pegylated interferon therapy was well tolerated by the treatment group with no premature discontinuation secondary to adverse e ects However the mean drop in haemoglobin over the treatment course was signifi cantly greater in the treatment group 4 32 g L SD 2 47 than in the comparator group Total Treatment group Comparator group 14 day survival 28 day survival 0 10 20 30 40 50 21 44 14 20 p 0 004 7 24 6 20 10 44 4 24 60 70 80 Survival p 0 054 Figure 2 Survival from date of diagnosis of MERS CoV infection by patient group Log rank test Treatment group n 20 Comparator group n 24 p value Invasive ventilation 19 95 22 92 1 00 Extracorporeal membrane oxygenation 2 10 2 8 1 00 Prone positioning 4 22 1 5 0 18 Renal replacement therapy 12 60 10 42 0 23 Vasopressor therapy 14 70 18 75 0 71 Immunoglobulin therapy 0 0 Packed red blood cell transfusion 10 53 9 38 0 32 Corticosteroid therapy 11 58 12 50 0 71 Number of antibacterial therapy agents 5 5 2 5 4 58 1 5 0 134 Oseltamivir therapy 17 85 16 67 0 16 Data are number or mean SD Only 18 patients were assessed Only 19 patients were assessed Table 2 Support measures o ered during the course of Middle East respiratory syndrome coronavirus infection by patient group Articles Vol 14 November 2014 1093 2 14 g L 1 90 p 0 002 Mean minimum absolute neutrophil count was also signi fi cantly lower in the treatment group 2 99 10 L SD 1 87 compared with the comparator group 4 42 10 L 1 89 p 0 017 No other signifi cant di erences in laboratory indices between the two groups were noted during the treatment period table 3 Depression or acute confusion was not diagnosed in any of the patients in either group Discussion E ective treatment interventions for patients with severe MERS CoV infection are still urgently needed In critically ill patients with severe MERS CoV infection our study shows that ribavirin and pegylated interferon alfa 2a therapy is associated with a signifi cant 14 day survival benefi t compared with standard treatment 28 day survival also seemed to improve with ribavirin and pegylated interferon alfa 2a therapy but the di erence between groups was not signifi cant panel The loss of a signifi cant survival di erence over time might be partly explained by most patients in our cohort having several comorbidities with high APACHE II and SOFA scores Mortality is known to be very high in patients with severe MERS CoV infection who need critical care support 24 Therefore long term survival benefi t if present might be di cult to show in smaller studies Treatment with ribavirin and interferon was well tolerated in our study The only adverse event that was signifi cantly worse in the treatment group was mean decrease in haemoglobin 4 32 g L in the treatment group compared with 2 14 g L in the comparator group Anaemia is a well recognised complication of ribavirin therapy and was noted previously in studies investigating the role of ribavirin in the treatment of SARS coronavirus infection 25 26 Of note receipt of packed red blood cells was not signifi cantly di erent between the treatment and comparator groups in our study Furthermore no treatment discontinuations occurred as a result of anaemia Therefore the risk of ribavirin associated anaemia although substantial and in need of careful monitoring might not hinder the use of ribavirin for patients with severe MERS CoV infection especially if a survival benefi t can be confi rmed Baseline absolute neutrophil count was signifi cantly lower in the treatment group and therefore a signifi cantly lower minimal absolute neutrophil count during the course of the illness is not surprising Several investigators showed that interferon has useful in vitro activity against MERS CoV 13 20 26 However when compared with interferon and interferon interferon seems to have the most potent inhibitory in vitro activity against MERS CoV 21 Ribavirin has slight anti MERS CoV activity in vitro when used alone or in combination with interferon 13 22 Mycophenolic acid is another compound that exhibits signifi cant in vitro activity against MERS CoV 21 Of 290 compounds screened 60 were active in cell culture against MERS CoV 23 Although only the combination of interferon plus ribavirin has so far undergone in vivo assess ment against MERS CoV 14 many others are potential candidates for further clinical assessment One of the limitations of our study is its small size However only two previous reports of clinical use of ribavirin and interferon for MERS CoV infection have been published 18 19 In a retrospective report fi ve patients with severe MERS CoV infection all of whom had signifi cant comorbidities and needed mechanical ventilation received a com bination of ribavirin and pegylated interferon alfa 2b a median of 19 days after admission None of the patients survived and the investigators concluded that late commencement of therapy might not be benefi cial 18 In another report 19 a patient with severe MERS CoV infection received ribavirin and interferon therapy with good clinical response and no signifi cant adverse e ects Our study albeit small is the largest clinical investigation so far to assess the use of this combination in the treatment of patients with severe MERS CoV infection Although baseline characteristics of our treatment and comparator groups seem to be reasonably balanced substantial di erences might not be apparent because of the small number of patients in the study Our study is also limited by its retrospective non randomised nature Inevitably selection and unmeasured confounding bias cannot be completely excluded Undoubtedly new interventions should ideally be assessed in randomised controlled clinical trials However such an approach is generally accepted to not always be practically feasible in the context of an emerging and relatively uncommon disease such as MERS CoV infection 8 We carefully selected our comparator group ensuring that the two cohorts were matched as closely as possible in their clinical characteristics and treatment interventions other than Treatment group n 20 Comparator group n 24 p value Haemoglobin minimum g L 7 15 2 13 8 13 1 78 0 101 Haemoglobin change maximum g L 4 32 2 47 2 14 1 90 0 002 Peripheral white cell count minimum 10 L 5 04 3 36 5 71 2 08 0 421 Absolute neutrophil count minimum 10 L 2 90 1 87 4 42 1 89 0 017 Minimum lymphocyte count minimum 10 L 1 07 2 55 0 53 0 29 0 310 Platelet count minimum 10 L 117 80 62 73 113 92 59 28 0 834 Alanine transaminase maximum IU L 139 35 189 63 152